Carboxylic acid compounds for use as surfactants

ABSTRACT

Compounds of formula (I)  
                 
or a salt or solvate thereof, wherein: x represents 0 or 1; y represents 0 or 1; 
     R 1  and R 2  independently represent —C 1-9  alkyleneC 1-6  fluoroalkyl, which fluoroalkyl moiety contains at least 1 fluorine atom and not more than 3 consecutive perfluorocarbon atoms and wherein the R 1  and/or R 2  moiety is optionally interrupted by an ether link, processes for their preparation, use of the compounds in the preparation of pharmaceutical formulations and the formulations are described.

This invention relates to novel surfactants and aerosol formulationsthereof for use in the administration of medicaments by inhalation.

The use of aerosols to administer medicaments has been known for severaldecades. Such aerosols generally comprise the medicament, one or morechlorofluorocarbon propellants and either a surfactant or a co-solvent,such as ethanol. The most commonly used aerosol propellants formedicaments have been propellant 11 (CCl₃F) and/or propellant 114(CF₂ClCF₂Cl) with propellant 12 (CCl₂F₂). However these propellants arenow believed to provoke the degradation of stratospheric ozone and thereis thus a need to provide aerosol formulations for medicaments whichemploy so called “ozone-friendly” propellants.

A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise fluorocarbons and hydrogen-containingchlorofluorocarbons, and a number of medicinal aerosol formulationsusing such propellant systems are disclosed in, for example, EP0372777,WO91/04011, WO91/11173, WO91/11495 and WO91/14422. These applicationsare all concerned with the preparation of pressurised aerosols for theadministration of medicaments and seek to overcome the problemsassociated with the use of the new class of propellants, in particularthe problems of stability associated with the pharmaceuticalformulations prepared. The applications all propose the addition of oneor more of adjuvants such alcohols, alkanes, dimethyl ether, surfactants(including fluorinated and non-fluorinated surfactants, carboxylicacids, polyethoxylates etc) and even conventional chlorofluorocarbonpropellants in small amounts intended to minimise potential ozonedamage.

It is essential that the prescribed dose of aerosol medication deliveredfrom the MDI to the patient consistently meets the specificationsclaimed by the manufacturer and comply with the requirements of the FDAand other regulatory authorities. That is, every dose delivered from thecan must be the same within close tolerances. Therefore it is importantthat the formulation be substantially homogenous throughout theadministered dose at the time of actuation of the metering valve.

In the case of suspension formulations, to control aggregation of fineparticles and thereby influence the dispersability of the suspension, itis well established in the art that fluorinated surfactants may be usedto stabilise micronised drug suspensions in fluorocarbon propellantssuch as 1,1,1,2-tetrafluoroethane (P134a) or1,1,1,2,3,3,3-heptafluoro-n-propane (P227), see for example U.S. Pat.No. 4,352,789, U.S. Pat. No. 5,126,123, U.S. Pat. No. 5,376,359, U.S.application Ser. No. 09/580,008, WO91/11173, WO91/14422, WO92/00062 andWO96/09816.

WO92/00061 discloses non-fluorinated surfactants for use withfluorocarbon propellants.

Surprisingly, the applicants have now found that a particular group ofnovel low fluorine content compounds with good surfactant properties maybe used to prepare novel aerosol formulations, and can be advantageousin terms of improving the stability of the aerosol formulation, reducingdrug deposition, increasing shelf life and the like. In addition thecompounds of the invention are adequately soluble in the fluorocarbon orhydrogen-containing chlorofluorocarbon propellants or mixtures thereof,obviating the need to use a polar adjuvant.

Thus, the invention provides a compound of formula (I)

or a salt or solvate thereof, wherein:

-   x represents 0 or 1;-   y represents 0 or 1;-   R¹ and R² independently represent —C₁₋₉ alkyleneC₁₋₆ fluoroalkyl,    which fluoroalkyl moiety contains at least 1 fluorine atom and not    more than 3 consecutive perfluorocarbon atoms and wherein said R¹    and/or R² moiety is optionally interrupted by an ether link.

Examples of R¹ include —Cl alkylene-O—C₁₋₃ fluoroalkyl, such as—(CH₂)₂—O—CF₃ or —(CH₂)₂—O—CF₂CF₃ and —C₁₋₃ alkylene-O—C₁₋₃ alkyleneC₁₋₃fluoroalkyl such as —(CH₂)₂—O—CH₂CF₃ or —(CH₂)₂—O—CH₂CF₂CF₃.

Examples of R² include —C₁₋₆ alkylene-O—C₁₋₃ fluoroalkyl, such as—(CH₂)₂—O—CF₃ or —(CH₂)₂—O—CF₂CF₃ and —C₁₋₃ alkylene-O—C₁₋₃ alkyleneC₁₋₃fluoroalkyl such as —(CH₂)₂—O—CH₂CF₃ or —(CH₂)₂—O—CH₂CF₂CF₃.

In one aspect the invention provides a compound of formula (II)

wherein R¹ and R² are as defined above.

In another aspect the invention provides a compound of formula (III)

wherein R¹ and R² are as defined above.

In the embodiments of the invention preferably R¹ and R² independentlyrepresent —C₁₋₉alkyleneC₁₋₆ fluoroalkyl, which fluoroalkyl moietycontains at least 1 fluorine atom and not more than 3 consecutiveperfluorocarbon atoms.

More preferably R¹ represents —C₁ alkyleneC₁₋₃ fluoroalkyl morepreferably —C₁₋₃ alkyleneC₁₋₃ fluoroalkyl, especially —C₂ alkyleneC₁₋₂fluoroalkyl, particularly —CH₂CH₂CF₂CF₃.

More preferably R² represents —C₁₋₆ alkyleneC₁₋₃ fluoroalkyl morepreferably —C₁₋₃ alkyleneC₁₋₃ fluoroalkyl, especially —C₂ alkyleneC₁₋₂fluoroalkyl, particularly —CH₂CH₂CF₂CF₃.

Most preferably R¹ represents the same as R².

Preferably x represents 1.

Preferably y represents 1.

Preferably x represents the same as y.

Salts include alkali metal salts such as sodium and potassium andtertiary alkyl ammonium salts such as tert-butyl ammonium.

Preferably compounds of formula (I), (II) or (III) will be present asthe free acid.

Compounds of formula (I), (II) or (III) contain one or more chiralcentres. It will be understood that compounds of formula (I), (II) or(III) include all optical isomers of the compounds of formula (I), (II)or (III) and mixtures thereof, including racemic mixtures thereof.

In a further aspect the invention provides a pharmaceutical aerosolformulation which comprises particulate medicament, a fluorocarbon orhydrogen-containing chlorofluorocarbon propellant, or mixtures thereof,and a compound of formula (I) as described above.

The compounds of formula (I), (II) or (III) employed for the preparationof formulations according to the present invention are effectivestabilisers at low concentrations relative to the amount of medicament.Thus, the amount of compound of formula (I), (II) or (III) employed isdesirably in the range of 0.05% to 20% w/w, particularly 0.5% to 10%w/w, more particularly 0.5% to 5% w/w, relative to the medicament.

The particle size of the particulate (e.g. micronised) medicament shouldbe such as to permit inhalation of substantially all of the medicamentinto the lungs or nasal cavity upon administration of the aerosolformulation and will thus be less than 100 microns, desirably less than20 microns, and preferably will have a mass median aerodynamic diameter(MMAD) in the range 1-10 microns, e.g. 1-5 microns.

The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

Medicaments which may be administered in aerosol formulations accordingto the invention include any drug useful in inhalation therapy and whichmay be presented in a form which is substantially completely insolublein the selected propellant. Appropriate medicaments may thus be selectedfrom, for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;anti-allergics, e.g. cromoglycate (e.g. as sodium salt), ketotifen ornedocromil (e.g. as sodium salt); antiinfectives e.g. cephalosporins,penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine;anti-histamines, e.g. methapyrilene; anti-inflammatories, e.g.beclomethasone (e.g. as dipropionate), fluticasone (e.g. as propionate),flunisolide, budesonide, rofleponide, mometasone furoate, ciclesonide,triamcinolone acetonide or 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; anti-tussives, e.g.noscapine; bronchodilators, e.g. albuterol (e.g. as free base or assulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride),rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol,4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)pro-pyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;diuretics, e.g. amiloride; anti-cholinergics, e.g. ipratropium (e.g. asbromide), tiotropium, atropine or oxitropium; hormones, e.g. cortisone,hydrocortisone or prednisolone; xanthines, e.g. aminophylline, cholinetheophyllinate, lysine theophyllinate or theophylline; therapeuticproteins and peptides, e.g. insulin or glucagon. It will be clear to aperson skilled in the art that, where appropriate, the medicaments maybe used in the form of salts, (e.g. as alkali metal or amine salts or asacid addition salts) or as esters (e.g. lower alkyl esters) or assolvates (e.g. hydrates) to optimise the activity and/or stability ofthe medicament and/or to minimise the solubility of the medicament inthe propellant. It will be further clear to a person skilled in the artthat where appropriate, the medicaments may be used in the form of apure isomer, for example, R-albuterol or RR-formoterol.

Particularly preferred medicaments for administration using aerosolformulations in accordance with the invention include anti-allergics,bronchodilators and anti-inflammatory steroids of use in the treatmentof respiratory disorders such as asthma, COPD or rhinitis by inhalationtherapy, for example cromoglycate (e.g. as sodium salt), albuterol (e.g.as free base or sulphate), salmeterol (e.g. as xinafoate), formoterol(e.g. as fumarate), terbutaline (e.g. as sulphate), reproterol (e.g. ashydrochloride), a beclomethasone ester (e.g. as diproprionate), afluticasone ester (e.g. as propionate). Salmeterol, especiallysalmeterol xinafoate, albuterol sulphate, fluticasone propionate,beclomethasone dipropionate and physiologically acceptable salts andsolvates thereof are especially preferred.

It will be appreciated by those skilled in the art that the aerosolformulations according to the invention may, if desired, contain acombination of two or more active ingredients. Thus suitablecombinations include bronchodilators (e.g. albuterol or isoprenaline) incombination with an anti-inflammatory steroid (e.g. beclomethasoneester); a bronchodilator in combination with an anti-allergic (e.g.cromoglycate). Exemplary combinations also include: ephedrine andtheophylline; fenoterol and ipratropium; isoetharine and phenylephrine;albuterol (e.g. as free base or as sulphate) and beclomethasone ester(e.g. as dipropionate); budesonide and formoterol (e.g. as fumarate)which is of particular interest; and salmeterol (particularly assalmeterol xinafoate) and fluticasone ester (e.g. as propionate) also ofparticular interest.

The propellants for use in the invention may be any fluorocarbon orhydrogen-containing chlorofluorocarbon or mixtures thereof having asufficient vapour pressure to render them effective as propellants.Preferably the propellant will be a non-solvent for the medicament.Suitable propellants include, for example, C₁₋₄hydrogen-containingchlorofluorocarbons such as CH₂ClF, CClF₂CHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl and CClF₂CH₃; C₁₋₄hydrogen-containing fluorocarbonssuch as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbonssuch as CF₃CF₃ and CF₃CF₂CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of the aboveidentified compounds, preferably binary mixtures, with otherfluorocarbons or hydrogen-containing chlorofluorocarbons, for example,CHClF₂, CH₂F₂ and CF₃CH₃. Particularly preferred as propellants areC₁₋₄hydrogen-containing fluorocarbons such as 1,1,1,2-tetrafluoroethane(CF₃CH₂F) and 1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) ormixtures thereof. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellante.g. 1,1,1,2-tetrafluoroethane (HFA 134a) or1,1,1,2,3,3,3-heptafluoro-n-propane (HFA 227), especially1,1,1,2-tetrafluoroethane.

It is desirable that the formulations of the invention contain nocomponents which may provoke the degradation of stratospheric ozone. Inparticular it is desirable that the formulations are substantially freeof chlorofluorocarbons such as CCl₃F, CCl₂F₂ and CF₃CCl₃.

If desired the propellant may additionally contain a volatile adjuvantsuch as a saturated hydrocarbon, for example, propane, n-butane,isobutane, pentane and isopentane or a dialkyl ether, for example,dimethyl ether. In general, up to 50% w/w of the propellant may comprisea volatile hydrocarbon, for example 1 to 30% w/w. However, formulationswhich are substantially free of volatile adjuvants are preferred. Incertain cases, it may be desirable to include appropriate amounts ofwater, which can be advantageous in modifying the dielectric propertiesof the propellant.

Polar adjuvants which may if desired, be incorporated into theformulations according to the present invention include, for example,C₂₋₆aliphatic alcohols and polyols such as ethanol, isopropanol andpropylene glycol and mixtures thereof. Preferably ethanol will beemployed. In general only small quantities (e.g. 0.05 to 3.0% w/w) ofpolar adjuvants are required and the use of quantities in excess of 5%w/w may disadvantageously tend to dissolve the medicament. Formulationspreferably contain less than 1% w/w, e.g. about 0.1% w/w of polaradjuvant. Polarity may be determined, for example, by the methoddescribed in European Patent Application Publication No. 0327777.

However as the compounds of formula (I), (II) or (III) are adequatelysoluble in the fluorocarbon or hydrogen-containing chlorofluorocarbonpropellant the need to use a polar adjuvant is obviated. This isadvantageous as polar adjuvants especially ethanol are not suitable foruse with all patient groups. Formulations containing a compound offormula (I), (II) or (III) which avoid use of a polar adjuvant arepreferred.

In addition to one or more compounds of the general formula (I), (II) or(III) the formulations according to the present invention may optionallycontain one or more further ingredients conventionally used in the artof pharmaceutical aerosol formulation. Such optional ingredientsinclude, but are not limited to, taste masking agents, sugars, buffers,antioxidants, water and chemical stabilisers.

A particularly preferred embodiment of the invention provides apharmaceutical aerosol formulation consisting essentially of one or moreparticulate medicament(s), one or more fluorocarbon orhydrogen-containing chlorofluorocarbon propellant(s) and one or morecompound(s) of formula (I), (II) or (III).

A further embodiment of the invention is a sealed container capable ofwithstanding the pressure required to maintain the propellant as aliquid, such as a metered dose inhaler, containing therein the aerosolformulation as described above.

The term “metered dose inhaler” or MDI means a unit comprising a can, asecured cap covering the can and a formulation metering valve situatedin the cap. MDI system includes a suitable channelling device. Suitablechannelling devices comprise, for example, a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient, for example, using a mouthpiece actuator.

As an aspect of this invention there are also provided processes for thepreparation of compounds of formula (I), (II) or (III).

Therefore a process for preparing a compound of formula (I) is providedwhich comprises:

-   (a) oxidation of a compound of formula (IV)    or a salt or solvate thereof, wherein R¹, R², x, and y are as    defined above; or-   (b) deprotection of a derivative of a compound of formula (I) in    which the carboxylic acid group is protected.

In process (a) methods for oxidising a primary alcohol to thecorresponding carboxylic acid, using strong oxidising agents, are wellknown to persons skilled in the art.

Suitable reagents include chromic acid as described in Chem. Pharm.Bull. 21 (10) 2265-2267 (1973), permanganate e.g. potassiumpermanganate, nitric acid, acidic chromiun trioxide and2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO). Permanganateis preferred for use in process (a), especially potassium permanganate.The oxidation will generally take place in water at a non-extremetemperature, for example, 0 to 100° C. such 70° C.

In process (b) examples of carboxylic acid protecting groups and meansfor their removal can be found in “Protecting Groups In OrganicSynthesis” by Theodora Green and Peter G. M Wuts (John Wiley and SonsInc 1999). Suitable carboxylic acid protecting groups include but arenot limited to carboxylic acid esters e.g. t-butyl esters,2,2,2-trichloroethyl esters, aryl esters, benzyl esters includingp-nitrobenzyl esters. Protecting groups may be removed by acid or basecatalysed hydrolysis or by catalytic hydrogenolysis. Where thecarboxylic acid is protected as a benzyl ester, the protecting group maybe removed, for example, by hydrogenolysis. Where the carboxylic acid isprotected as a t-butyl ester, the protecting group may be removed, forexample, by hydrolysis with trifluoroacetic acid. Where the carboxylicacid is protected as a 2,2,2-trichloroethyl ester, the protecting groupmay be removed, for example, using zinc and acetic acid. Whereappropriate protecting groups will be chosen to ensure they can beselectively removed.

A process for preparing a compound of formula (IV) or a protectedderivative thereof comprises:

-   (c) preparing a compound of formula (IV) or a protected derivative    thereof (in which R² represents the same as R¹)    by reacting glycerol, or a derivative thereof wherein a primary    hydroxyl group is protected, with a compound of formula (V¹)    wherein R¹ and x are as defined above and L¹ represents a leaving    group or —OH; or-   (d) reacting a compound of formula (V¹)    or a derivative thereof wherein the primary hydroxyl is protected,    wherein R² and y are as defined above, with a compound of formula    (V¹) as defined above; or-   (e) reacting a compound of formula (V²)    wherein R² and y are as defined above and L² represents a leaving    group or H with a compound of formula (VI²)    or a derivative thereof wherein a primary hydroxyl is protected and    wherein R¹ and x are defined above; or-   (f) preparing a compound of formula (IV), or a protected derivative    thereof in which R² represents the same as R¹, by reacting a    compound of formula (VII)    or a derivative thereof in which the primary hydroxyl is protected,    wherein L³ and L⁴ independently represent a leaving group with an    acid of formula (V¹) wherein L¹ represents —OH, as defined above, or    a salt thereof; or-   (g) reacting a compound of formula (VIII¹)    or a derivative thereof in which the primary hydroxyl is protected,    wherein R¹ and x are as defined above and L⁵ represents a leaving    group, with an acid of formula (V²) wherein L² represents H, as    defined above, or a salt thereof; or-   (h) reacting a compound of formula (VIII²)    or a derivative thereof in which the primary hydroxyl is protected,    wherein R² and y are as defined above and L⁶ represents a leaving    group, with an acid of formula (V¹) wherein L¹ represents —OH, as    defined above, or a salt thereof; or-   (i) deprotecting a protected compound of formula (IV).

In each process the non-reacting hydroxyl group(s) will preferably beprotected, for example, as the benzyl or THP ether, especially whereinthe non-reacting hydroxyl is a primary hydroxyl as it may be thepreferred site of reaction.

Examples of protecting groups (e.g. for hydroxyl) and means for theirremoval can be found in “Protecting Groups In Organic Synthesis” byTheodora Green and Peter G. M Wuts (John Wiley and Sons Inc 1999).Suitable hydroxylprotecting groups include, but are not limited to,carboxylic acid esters e.g. acetate ester, aryl esters, benzoate esters,ethers e.g. benzyl ether and p-methoxybenzyl ether, tetrahydropyranylether and silyl ethers e.g. tert-butyldimethylsilyl ether. Preferablyhydroxyl groups are protected as the benzyl ether or thetetrahydropyranyl (THP) ether. Especially preferred is the benzyl ether.

Protecting groups can be removed by acid or base catalysed hydrolysis orcatalytic hydrogenolysis. Silyl ethers may require hydrogen fluoride ortetrabutylammonium fluoride to be cleaved. Where a hydroxyl is protectedas the benzyl ether, the protecting group may be removed, for example,by hydrogenolysis. Where a hydroxyl is protected as the THP ether, theprotecting group may be removed, for example, by acid hydrolysis. Whereappropriate protecting groups will be chosen to ensure they can beselectively removed.

In process (c) suitable leaving groups for L¹ include halogen, forexample, chloride and anhydride, which may be prepared, for example,using the triethylamine salt of a —C₁₋₃ alkyl acid using methodology asdescribed in Tetrahedron 1960, 11, 39. Preferably L¹ represents —OH. Theprocess is generally performed under basic conditions, for example, inthe presence of triethylamine or pyridine, in a suitable solvent, forexample, dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide(DMF) or similar, at a non-extreme temperature, for example, 0 to 50° C.such as room temperature. Where compounds of formula (V¹) are carboxylicacids i.e. where L¹ represents —OH a coupling agent, for example,hydroxybenzotriazole (HOBT), dicyclohexylcarbodiimide (DCC) oro-(7-azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluroniumhexafluorophosphate (HATU) together with diisopropylethylamine (DIPEA)may also be present. An alternative process which may providestereocontrol is described J Org Chem, 1998, 63, 6273. When R¹represents the same as R² usually at least two molar equivalents ofcompound of formula (V¹) will be used in this process. Preferably aexcess of compound of formula (V¹) will be used.

In processes (d) and (e), conditions analogous to those employed inprocess (c) are suitable. Suitable leaving groups for L², include thosedescribed above for L¹.

In process (e the reaction will generally take place in the presence ofa base, for example triethylamine or 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU), in a suitable inert solvent, for example, dichloromethane (DCM),dimethylformamide (DMF) or acetonitrile at non-extreme temperatures, forexample, −10 to 80° C. such as room temperature. Suitable leaving groupsfor L³ and L⁴ include halogen, for example chloride or bromide,—O-tosyl, —O-mesyl or —O-triflyl.

In processes (g) and (h) conditions analogous to those employed inprocess (f are suitable. Suitable leaving groups for L⁵ and L⁶ includethose defined above for L³.

Preferably non-reacting hydroxyl group(s) will be protected e.g. as abenzyl or a THP ether. Where there is more than one non-reactinghydroxyl group preferably each non-reacting hydroxyl will be protectedby different protecting groups to facilitate selective removal e.g.tetrahydropyranyl (THP) ether and benzyl ether. It is especiallyadvantageous that when the non-reacting hydroxyl is a primary alcohol itis protected as it may react preferentially to the desired site ofreaction.

However variations of these reactions where the leaving group and thereacting hydroxyl are swapped may also be contemplated. Leaving groupswill be used as necessary in these reactions.

Compounds of formula (VI¹), or a protected derivative thereof may beprepared by a process which comprises reacting a compound of formula(V²) with a selectively protected derivative of glycerol wherein theunreacting hydroxyl groups are protected. The reaction can be performedunder conditions analogous to those described above for process (c)described above.

Alternatively compounds of formula (VI¹) may be prepared by a processwhich comprises:

-   (j) reacting epibromohydrin or epichlorohydrin with a compound of    formula (V²) wherein L² represents —OH, as defined above, or a salt    thereof; and-   (k) reacting the product of step (j) with water.

Epoxides can be cleaved under acidic or basic conditions. The product ofthe reaction can be controlled by choice of the nucleophile and reactionconditions. The advantage of using an epihalohydrin is that the threecarbons in the starting material may be differentiated.

Usually reaction (j) will be performed in a suitable solvent, forexample, tetrahydrofuran (THF) at a non-extreme temperature, forexample, −10 to 50° C. such as 0° C. to room temperature.

Compounds of formula (VI²) may be prepared using analogous methods tothose described above for the preparation of compounds of formula (VI¹).

Compounds of formula (V) can be prepared from glycerol by converting thedesired hydroxyls into leaving groups using known methods. Reagents forconverting hydroxyl groups into good leaving groups include halogenatingagents such as carbon tetrabromide and triphenylphosphine, thionylchloride or phosphorus pentachloride or may be effected by treatmentwith methane sulphonyl chloride or p-toluene sulphonic chloride.Protecting groups will be used as necessary in these reactions.

Compounds of formula (VIII¹) may be prepared from compounds of formula(VI²), preferably a protected derivative thereof, using, for example, ahalogenating agent to convert the desired hydroxyl in the lattercompound into a good leaving group. Compounds of formula (VIII²) may beprepared from compounds of formula (VI¹) by analogous methods.

Compounds of formula (V¹) and (V²) are either known or may be preparedby known methods, for example, acids can be prepared by oxidation of thecorresponding alcohol and acid halides can be prepared by reacting thecorresponding acid with a halogenating agent such as thionyl chloride.

Variations of the above methods which are common in the art are withinthe scope of this invention.

Alternatively compounds of formula (I) may be prepared by a processwhich comprises: (L) reacting a protected derivative of glycidic acid,for example wherein the carboxylic acid moiety is protected as thebenzyl ester or p-nitrobenzyl ester, with an acid of formula (V²)wherein L² represents —OH, as defined above, or a salt thereof to give acompound of formula (IX)

wherein R² and y are as defined above and P¹ represents a protectinggroup;

-   (m) reacting the product of step (L) with an acid of formula (III¹)    wherein L¹ represents —OH or a salt thereof; and-   (n) followed, if necessary, by deprotection.

Process (L) may be performed using one molar equivalent of an acid offormula (V²) which may be in the presence of a catalytic amount of, forexample, sulphuric acid, toluene sulphonic acid or a Lewis acid such asBF₃ etherate, FeCl₃ or ZnCl₂ optionally in the presence of anappropriate solvent, for example DCM, DMF or THF, at a non-extremetemperature, for example, 0 to 100° C. such as room temperature forbetween 1 and 24 hours.

Process (m) may be performed under standard conditions in the presenceof a coupling agent as described above in process (c). Alternativelyprocess (m) may be performed under conditions as described for process(L) above however the reaction will usually be performed at anon-extreme temperature elevated temperature, for example 25 to 100° C.such as 50 to 70° C., for between 1 and 24 hours. Wherein the R¹represents the same as R² processes (L) and (m) may be combined to givea “one step” reaction wherein at least two molar equivalents of an acidof formula (V¹) are reacted at a non-extreme elevated temperature underanalogous conditions to those described above for process (L).

The deprotection in process (n) may be performed using hydrogenolysis.

Compounds of formula (VIII) are either known or may be prepared by knownmethods. Compounds of formula (IV), (VI¹), (VI²), (VIII¹), (VIII²) and(IX) are new and form an aspect of the invention.

In addition processes for preparing formulations including one or morecompounds of formula (I) form an aspect of this invention.

The formulations of the invention may be prepared by dispersal of themedicament and a compound of formula (I) in the selected propellant inan appropriate container, e.g. with the aid of sonication or ahigh-shear mixer. The process is desirably carried out under controlledhumidity conditions.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The suspension stability of the aerosol formulations according to theinvention may be measured by conventional techniques, for example, bymeasuring flocculation size distribution using a back light scatteringinstrument or by measuring particle size distribution by cascadeimpaction or by the “twin impinger” analytical process. As used hereinreference to the “twin impinger” assay means “Determination of thedeposition of the emitted dose in pressurised inhalations usingapparatus A” as defined in British Pharmacopaela 1988, pages A204-207,Appendix XVII C. Such techniques enable the “respirable fraction” of theaerosol formulations to be calculated. One method used to calculate the“respirable fraction” is by reference to “fine particle fraction” whichis the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above.

MDI canisters generally comprise a container capable of withstanding thevapour pressure of the propellant used such as a plastic orplastic-coated glass bottle or preferably a metal can, for example analuminium or an alloy thereof which may optionally be anodised,lacquer-coated and/or plastic-coated (e.g. incorporated herein byreference WO96/32099 wherein part or all of the internal surfaces arecoated with one or more fluorocarbon polymers optionally in combinationwith one or more non-fluorocarbon polymers), which container is closedwith a metering valve. The cap may be secured onto the can viaultrasonic welding, screw fitting or crimping. MDIs taught herein may beprepared by methods of the art (e.g., see Byron, above and WO96132099).Preferably the canister is fitted with a cap assembly, wherein aformulation metering valve is situated in the cap, and said cap iscrimped in place.

The metering valves are designed to deliver a metered amount of theformulation per actuation and incorporate a gasket to prevent leakage ofpropellant through the valve.

The gasket may comprise any suitable elastomeric material such as, forexample, low density polyethylene, chlorobutyl, black and whitebutadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitablevalves are commercially available from manufacturers well known in theaerosol industry, for example, from Valois, France (e.g. DF10, DF30,DF60), Bespak plc, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK(e.g. Spraymiser™).

A further aspect of this invention comprises a process for filling thesaid formulation into MDIs.

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The particulate medicament is added to acharge vessel and liquefied propellant is pressure filled through thecharge vessel into a manufacturing vessel, together with liquefiedpropellant containing the surfactant. The drug suspension is mixedbefore recirculation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.

In an alternative process, an aliquot of the liquefied formulation isadded to an open canister under conditions which are sufficiently coldto ensure the formulation does not vaporise, and then a metering valvecrimped onto the canister.

Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler system foradministration of the medicament into the lungs or nasal cavity of apatient. Metered dose inhalers are designed to deliver a fixed unitdosage of medicament per actuation or “puff”, for example, in the rangeof 10 to 5000 micrograms of medicament per puff.

Administration of medicament may be indicated for the treatment of mild,moderate, severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample, from 1 to 8 times per day, giving for example 1, 2, 3 or 4puffs each time.

Suitable daily doses, may be, for example, in the range 50 to 200micrograms of salmeterol, 100 to 1000 micrograms of albuterol, 50 to2000 micrograms of fluticasone propionate or 100 to 2000 micrograms ofbeclomethasone dipropionate, depending on the severity of the disease.

Thus, for example, each valve actuation may deliver 25 microgramsalmeterol, 100 microgram albuterol, 25, 50, 125 or 250 microgramfluficasone propionate or 50, 100, 200 or 250 microgram beclomethasonedipropionate. Doses for Seretide™, which is a combination of salmeteroland fluticasone propionate, will usually be those given for thecorresponding individual component drugs. Typically each filled canisterfor use in a metered dose inhaler system contains 60, 100, 120, 160 or240 metered doses or puffs of medicament.

An appropriate dosing regime for other medicaments will be know orreadily available to persons skilled in the art.

The use of the compounds of formula (I), (II) or (III) or mixturesthereof as described above as a surfactant, especially in thepreparation of a pharmaceutical formulation; use of a formulation asdescribed above in inhalation therapy e.g. for the treatment orprophylaxis of disease, particularly respiratory disorders; and use of ametered dose inhaler system in the treatment or prophylaxis ofrespiratory disorders are all alternative aspects of this invention.

A still further aspect of the present invention comprises a method oftreating respiratory disorders such as, for example, asthma and/or COPDwhich comprises administration by inhalation of an effective amount of aformulation as herein described.

The following non-limiting examples serve to illustrate the invention.

EXAMPLES

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solventA), and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0-0.7 min 0% B, 0.74.2 min 100% B, 4.2-5.3min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 ml/min. The mass spectrawere recorded on a flow injection Hewlett Packard engine usingthermospray positive ion mode or a Micromass series II mass spectrometerusing electrospray positive and negative mode (ES+ve and ES−ve).

Example 1 2,3-Bis[(4,4,5,5,5-pentafluoronentanoyl)oxy]propanoic Acid (a)4.4,5,5,5-Pentafluoropentanoic Acid

The title compound was synthesised by the method described in OrganicProcess Research and Development 1999, 3, 363-364.

(b)2-[(4,4,5,5,5-Pentafluoropentanoyl)oxy]-1-{[(phenylmethyl)oxy]methyl}ethyl4,4,5,5,5-pentafluoropentanoate

The product of step (a) (118 g) and carbonyl duimidazole (98.8 g) weredissolved in tetrahydrofuran (1900 mL) and stirred at 50° C. for 1 hour.A solution of D/L benzyl glycerol (50.0 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (92.7 g) in tetrahydrofuran (230 mL)was added over ten minutes and the reaction stirred at 50° C. for 2hours, before being allowed to cool to 20° C. The reaction mixture waspartitioned between methyl tert-butyl ether (2.36 L) and 1M hydrochloricacid (2.36 L). The aqueous layer was discarded and the organic layerwashed sequentially with water (2.36 L) and saturated sodium bicarbonatesolution (2.0 L). The organic phase was distilled out and diluted withmethyl tert-butyl ether (2.56 L). This was washed with brine (2.56 L),water (2.56 L), dried over magnesium sulphate and the solvent removed invacuo. Purification of the residue by column chromatography on silicagel (Biotage) eluting with 10:1 cyclohexane:ethyl acetate gave the titlecompound (110 g) as an orange/yellow oil.

Mass spectrum m/z 548 [MNH₄ ⁺]

(c)2-Hydroxy-1-{[(4.4,5,5,5-pentafluoropentanoyl)oxy]methyl}ethyl-4.4,5,5,5-pentafluoropentanoate

The product of step (b) (110 g) was dissolved in tetrahydrofuran (1100mL) and 10% Pd/C (11 g) was added. The reaction was placed under anatmosphere of hydrogen and stirred at 20° C. for 15 hours. The reactionmixture was filtered through a bed of celite and the solvent was removedin vacuo to give the title compound (97.6 g) as a light yellow oil.

Mass spectrum m/z 458 [MNH₄ ⁺]

(d) 2,3-Bis[(4.4.5,5,5-pentafluoronentanoyl)oxy]propanoic Acid

The product of step (c) (300 mg) and tetraethylammonium hydrogensulphate (1.5 mg) were dissolved in water (3 mL) and heated withstirring to 70° C. To this solution was added dropwise a solution ofsodium permanganate (152 mg) in water (2 mL). Once the addition wascomplete the reaction was stirred at 70° C. for 4 hours and then at 20°C. for 17 hours. The reaction mixture was filtered through a pad ofCelite. The resulting solution was partitioned between dichloromethane(150 mL) and water (150 mL). The aqueous layer was acidified to pH 1 bythe addition of 2M hydrochloric acid and then extracted withdichloromethane (3×150 mL). The combined organic layers were dried overmagnesium sulphate and the solvent removed in vacuo. Purification byIsolute NH₂ SPE cartridge, eluting with 2M ammonia in methanol gave thetitle compound as a clear oil (24 mg).

Mass spectrum m/z 453 [M⁻] LC Retention time 3.59 mins

Experimental Data

Salmeterol xinafoate formulations in HFA 134a, of strength 25 μg peractuation, and 10% w/w (relative to drug) of the relevant surfactantcompound of formula (I) were prepared in crimped glass bottles usingsalmeterol xinafoate (8.7 mg), HFA 134a (18 g) and the relevant compound(0.87 mg). The control was prepared without the addition of asurfactant.

Particle Size

Table 1 shows mean particle size data determined by image analysis usinga Galai CIS-100 particle size analyser for sample formulations preparedas described above. In this measurement, particle size is represented asthe equivalent diameter of a circle of equal area to the object. Themean is the average of 4 determinations. The particle size measurementwas obtained by transferring the suspensions to a pressurised cell, andvideo-imaging the sample under shear via a microscope objective.

The equivalent diameter is defined as the diameter of a circle of equalarea to the object.$\text{Equivalent~~Diameter} = \sqrt{\frac{\text{Area}}{\pi}}$

The mean equivalent diameter can be weighted by number, length orvolume. e.g. For three particles with equivalent diameters of x, y andz:$\text{Mean~~Number~~weighted~~diameter} = {{\left( \frac{1}{3} \right)x} + {\left( \frac{1}{3} \right)y} + {\left( \frac{1}{3} \right)z}}$$\text{Mean~~Length~~weighted~~diameter} = {{\left( \frac{x}{x + y + z} \right)x} + {\left( \frac{y}{x + y + z} \right)y} + \quad{\left( \frac{z}{x + y + z} \right)z}}$

The data shows that the surfactant compound of Example 1 has suspensionstabilising properties, thereby discouraging flocculation of drugparticles. This is seen by the reduction in average particle size (“meanlength weighted diameter”) when the said compound is incorporated intothe formulation. Furthermore, the standard deviation and the relativestandard deviation for the formulations incorporating the compound ofExample 1 are advantageously reduced. TABLE 1 Particle Size Data MeanLength Standard Relative weighted Deviation Standard diameter μm μmDeviation Control 29.3 1.7 5.7 Example 1 21.5 1.1 5.3Andersen Cascade Impaction Data

The formulation, the preparation of which is described above, wasprofiled using an Andersen Cascade Impactor. Ten actuations at“beginning of use” (BoU) were collected in the impactor from an inhalerafter 4 priming actuations were fired to waste. The drug delivered wasthen quantified by HPLC analysis. Testing was performed at the initialtimepoint (following sample preparation). The results, in Table 2 areshown as the mean analysis of 3 cans/inhalers.

The profile obtained was used to determine total dose emitted dose(ex-valve and ex-actuator) and the fine particle mass (FPM, defined asthe sum of stages 3-5). The percentage fine particle mass expresses theFPM as a percentage of the total dose emitted (ex-valve). The FPM isused as a measure of the proportion of the drug likely to reach thetherapeutic target in the lungs.

The data shows, that in the presence of the surfactant compound ofExample 1, there is an increase in both the absolute doses emitted andthe absolute FPM. There is also a significant increase in the percentageFPM. TABLE 2 Total Ex-Valve & Ex-actuator Emitted Dose and FPM DataUsing Cascade Impaction Total Dose Total Dose Emitted Emitted (Ex- FPMTimepoint (Ex-Valve) Actuator) μg μg % FPM Control Initial 23.3 20.3 9.942.6 Example 1 Initial 23.9 21.1 12.0 50.3Content Uniformity

The content uniformity of the formulation, the preparation of which isdescribed above, was assessed by dose through use testing. Testing wasperformed on 10 cans/inhalers at “beginning of use” (BoU) and “end ofuse” (EoU). After each inhaler had been primed (4 shots fired to waste),actuations 1 and 2 (BoU) were collected. The next 116 actuations of eachinhaler were then fired to waste using an automated method andactuations 119 and 120 (EoU) collected.

Assessment of content uniformity was performed at the initial timepoint(following sample preparation). Mean results from the two BoU actuations(1+2 for 10 inhalers) and the two EoU actuations (119+120 for same 10inhalers) together with the percentage relative standard deviation (%RSD) for the 10 cans are shown in Table 3. The data shows, that in thepresence of the surfactant compound of Example 1, there is in increasein the emitted BoU dose and a reduction in the EoU % RSD. The presenceof the surfactant therefore improves the content uniformity of theinhaler. Furthermore the formulations containing the compound of Example1, advantageously, show a reduction in the relative standard deviationat the BoU and EoU. TABLE 3 Control Example 1 BoU dose EoU dose BoU doseEoU dose Timepoint μg μg μg μg Initial 20.1 24.8 21.2 25.1 (2.6% RSD)(5.6% RSD) (1.7% RSD) (3.5% RSD)

1. A compound of formula (I)

or a salt or solvate thereof, wherein: x represents 0 or 1; y represents0 or 1; R¹ and R² independently represent —C₁₋₉alkyleneC₁₋₆fluoroalkyl,which fluoroalkyl moiety contains at least 1 fluorine atom and not morethan 3 consecutive perfluorocarbon atoms and wherein said R¹ and/or R²moiety is optionally interrupted by an ether link.
 2. A compoundaccording to claim 1, wherein R¹ is —C₁₋₆alkyleneC₁₋₃fluoroalkyl.
 3. Acompound according to claim 1, wherein R² is—C₁₋₆alkyleneC₁₋₃fluoroalkyl.
 4. A compound according to claim 1,wherein x represents
 1. 5. A compound according to claim 1, wherein yrepresents
 1. 6. A compound according claim 1, which is2,3-Bis[(4,4,5,5,5-pentafluoropentanoyl)oxy]propanoic acid.
 7. Apharmaceutical aerosol formulation which comprises particulatemedicament, a fluorocarbon or hydrogen-containing chlorofluorocarbonpropellant, or mixtures thereof, and a compound of formula (I) accordingto claim
 1. 8. A pharmaceutical formulation according to claim 7,wherein the amount of compound of formula (I) is in the range 0.5% to 5%w/w, relative to the medicament.
 9. A metered dose inhaler containing aformulation according to claim
 7. 10. (canceled)
 11. (canceled)
 12. Aprocess for the preparation of compounds of formula (I) comprising(a)oxidation of a compound of formula (IV)

or a salt or solvate thereof, wherein: x represents 0 or 1; y represents0 or 1; R¹ and R² independently represent —C₁₋₉ alkyleneC₁₋₆fluoroalkyl, which fluoroalkyl moiety contains at least 1 fluorine atomand not more than 3 consecutive perfluorocarbon atoms and wherein saidR¹ and/or R² moiety is optionally interrupted by an ether link; or (b)deprotection of a derivative of a compound of formula (I) in which thecarboxylic acid group is protected.
 13. A compound according to claim 1,wherein R¹ is —C₁₋₃alkyleneC₁₋₃fluoroalkyl.
 14. A compound according toclaim 1, wherein R¹ is —C₂alkyleneC₁₋₂fluoroalkyl.
 15. A compoundaccording to claim 1, wherein R¹ is —CH₂CH₂CF₂CF₃.
 16. A compoundaccording to claim 13, wherein R² is —C₁₋₃alkyleneC₁₋₃fluoroalkyl.
 17. Acompound according to claim 13, wherein R² is—C₂alkyleneC₁₋₂fluoroalkyl.
 18. A compound according to claim 13,wherein R² is —CH₂CH₂CF₂CF₃.
 19. A compound according to claim 1,wherein x is 1 and y is
 1. 20. A method of treating a respiratorydisorder in a subject in need thereof comprising administering byinhalation an effective amount of a formulation according to claim 7 tothe subject.